Association of a TRAF1 and a STAT4 gene polymorphism with increased risk for rheumatoid arthritis in a genetically homogeneous population

Department of Medicine, University of Crete, and Department of Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece.
Human Immunology (Impact Factor: 2.14). 08/2008; 69(9):567-71. DOI: 10.1016/j.humimm.2008.06.006
Source: PubMed


Rheumatoid arthritis (RA) is a multifactorial disease that is increasing in incidence worldwide. It is associated with a complex mode of inheritance, with many genes being involved in the development and progression of the disease. Genome-wide association studies in different populations have recently revealed a significant association between a TRAF1/C5 and a STAT4 polymorphism and the development of RA. In the present study we performed a case-control study in the population of the island of Crete, Greece, aiming to replicate the former findings in a genetically homogeneous cohort of patients. We found that mutated allele A or genotypes A/A and G/A of the TRAF1/C5 rs10818488 SNP were more common in individuals with RA than in control individuals (odds ratio [OR]=1.7, 95% confidence interval [CI]=1.35-2.15, and OR=2.22, 95% CI=1.61-3.05, respectively). Similarly, mutated allele T or genotypes T/T and G/T of the STAT4 rs7574865 SNP were also associated with susceptibility to RA (OR=1.9, 95% CI=1.46-2.50, and OR=2.37, 95% CI 1.73-2.25, respectively). Thus, we conclude that mutant alleles or genotypes of both polymorphisms examined are associated with the development of RA in our population.

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    • "IMBIO-51310; No. of Pages 13 6 R. Elshazli, A. Settin / Immunobiology xxx (2015) xxx–xxx Fig. 2. Odds ratios and 95% confidence intervals (CIs) of individual studies and of pooled data for the association between the T allele of PTPN22 polymorphism and RA. 2012; Palomino-Morales et al., 2010); and genotype frequencies that are not in HWE in control groups (Zervou et al., 2008) (Table 3). "
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    ABSTRACT: Rheumatoid arthritis (RA) is a common autoimmune disease with a complex genetic background. The genes encoding protein tyrosine phosphatase non-receptor type 22 (PTPN22) and signal transducer and activator of transcription 4 (STAT4) have been reported to be associated with RA in several ethnic populations. This work aims to assess the association between PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with RA susceptibility through an updated meta-analysis of available case-control studies. A literature search of all relevant studies published from January 2007 up to December 2014 was conducted using Pubmed and Science Direct databases. The observed studies that were related to an association between PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with RA susceptibility were identified. Meta-analyis of the pooled and stratified data was done and assessed using varied genetic models. Thirty-seven case-control studies with a total of 47 comparisons (29 for PTPN22 rs2476601 polymorphism and 18 for STAT4 rs7574865 polymorphism) met our inclusion criteria. The meta-analysis showed an association between PTPN22 T allele, CT+TT and TT genotypes with RA susceptibility. Furthermore, The meta-analysis showed an association between STAT4 T allele, GT+TT and TT genotypes with RA susceptibility. Stratification of RA patients according to ethnic groups showed that PTPN22 T allele, CT+TT genotypes, STAT4 T allele and STAT4 GT+TT were significantly associated with RA in European, Asian, African subjects, while PTPN22 TT genotype was significantly associated with RA in European but not in Asian and African subjects and STAT4 TT genotype was significantly associated with RA in European and Asian but not in African subject. A subgroup analysis according to the presence or absence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies revealed that the association between PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms with RA susceptibility may not be dependent on RF and anti-CCP antibodies. Our meta-analysis demonstrated that PTPN22 rs2476601 and STAT4 rs7574865 polymorphisms confers susceptibility to RA in total subjects and in major ethnic groups. The association may not be dependent on RF and anti-CCP antibodies. Copyright © 2015 Elsevier GmbH. All rights reserved.
    Immunobiology 04/2015; DOI:10.1016/j.imbio.2015.04.003 · 3.04 Impact Factor
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    • "Since Th1 and Th17 lineages are crucial effectors in chronic inflammatory disorders, STAT4 gene may play an important role in the pathogenesis of autoimmune diseases. To date, the SNP rs7574865 in STAT4 gene has been reported to be associated with an increased risk for diverse complex autoimmune diseases in different ethnic populations, such as RA [9] [10] [11] [12] [13]. Knowing that the allelic frequencies of genes often differ substantially between populations; we were interested to test the association 0198-8859/Ó 2014 American Society for Histocompatibility and Immunogenetics. "
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    ABSTRACT: Background: The gene encoding signal transducer and activator of transcription 4 (STAT4) has been reported to be associated with rheumatoid arthritis (RA) in several populations. This work aimed at assessing the association of STAT4 G>T gene polymorphism with the susceptibility, activity and functional disability of RA in Egyptian subjects. Subjects and methods: This study included 112 unrelated RA Egyptian patients who were compared to 122 healthy unrelated individuals taken from the same locality. For all subjects, DNA was genotyped for STAT4 G>T (rs7574865) polymorphism using the PCR-RFLP technique. Antibodies to cyclic citrullinated peptides (anti-CCP) were measured by enzyme-linked immunosorbent assay (ELISA). Results: Cases showed a significantly higher frequency of the STAT4 T allele carriage (GT+TT genotypes) compared to controls (51.8% vs. 31.1%, OR = 2.37, 95% CI = 1.39-4.05, p = 0.001). Also the frequency of the STAT4 T allele was significantly higher among cases compared to controls (30.4% vs. 16.8%, OR = 2.16, 95% CI = 1.39-3.35, p = 0.001). Cases positive to the STAT4 T allele (GT+TT genotypes) showed no significant difference compared to those with the GG genotype regarding their clinical and immune parameters. Nonetheless, they showed a more functional disability presented in their significantly higher health assessment questionnaire (HAQ) score (p = 0.02). Conclusions: This study gives an extra evidence to the association of the STAT4 T allele with the susceptibility and functional disability of RA.
    Human Immunology 06/2014; 75(8). DOI:10.1016/j.humimm.2014.06.013 · 2.14 Impact Factor
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    • "The cohort of the Cretan RA patients analyzed in the present work is a part of the Hellenic Biologic Registry for Rheumatic Diseases that collects data from all patients who receive biologic agents in 7 Rheumatology Centers of Greece. Considering that independent replication is required to confirm definitively the association of SNPs with response to anti-TNF therapy, we performed the present study focusing on the genetic homogeneous population of Crete, which shares a common genetic and cultural background and a common environment, while it is characterized by good genealogical and clinical records and low migration rates, thus contributing to an increased reliability of the data collected [23–25]. However, our study failed to detect any association between seven SNPs and response to anti-TNF therapy. "
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    ABSTRACT: Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. However, a significant subset of patients does not respond to anti-TNF agents, for reasons that are still unknown. The aim of this study was to validate five single nucleotide polymorphisms (SNPs) of PTPRC, CD226, AFF3, MyD88 and CHUK gene loci that have previously been reported to predict anti-TNF outcome. In addition, two markers of RA susceptibility, namely TRAF1/C5 and STAT4 were assessed, in a cohort of anti-TNF-treated RA patients, from the homogeneous Greek island of Crete, Greece. The RA patient cohort consisted of 183 patients treated with either of 3 anti-TNF biologic agents (infliximab, adalimumab and etanercept) from the Clinic of Rheumatology of the University Hospital of Crete. The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms (RFLPs) approach. Disease activity score in 28 joints (DAS28) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP. None of the 7 genetic markers correlated with treatment response. We conclude that the gene polymorphisms under investigation are not strongly predictive of anti-TNF response in RA patients from Greece.
    PLoS ONE 02/2013; 8(9):e74375. DOI:10.1371/journal.pone.0074375 · 3.23 Impact Factor
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